Synthesis of 5-benzyloxy-1,4-dihydro-6-methyl-4-oxopyridine-3-carbaldehyde by aerobic oxidation of the 5-dimethylaminomethyl analogue: optimisation of the reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2010.01.027

A successful introduction of the formyl group at position 5 of 3-hydroxypyridin-4-one was achieved by aerobic oxidation, catalysed by NHS/Co(II). To obtain a practical yield, the reaction conditions were optimised.

Full text of DOI:10.1016/j.tetlet.2010.01.027

Tetrahedron Letters 51 (2010) 1415–1418
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5-benzyloxy-1,4-dihydro-6-methyl-4-oxopyridine-3-carbaldehyde
by aerobic oxidation of the 5-dimethylaminomethyl analogue: optimisation
of the reaction conditions
*
Yong Min Ma, Robert C Hider
Pharmaceutical Science Division, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A successful introduction of the formyl group at position 5 of 3-hydroxypyridin-4-one was achieved by
aerobic oxidation, catalysed by NHS/Co(II). To obtain a practical yield, the reaction conditions were
optimised.
Received 27 October 2009
Revised 21 December 2009
Accepted 8 January 2010
Available online 14 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Of the three hydroxypyridinone classes, the 3-hydroxypyridin-
4-ones (HPOs) possess the highest iron(III) affinity.1 This is attrib-
uted to the extensive delocalisation of the lone pair of electrons
associated with N1 of the heterocyclic ring through the ring to
the oxygen at C4 leading to a relatively high pKa value.1 One of
these compounds, 1,2-dimethyl-3-hydroxypyridin-4-one (deferi-
prone), is used clinically for the treatment of iron overload. How-
ever, the dose required to keep patients in negative iron balance
is high2 due to extensive metabolism in the liver.3 Furthermore,
side effects have also been reported in some patients receiving this
drug.4,5 Thus a metabolically stable and less toxic substitute is ur-
gently required at the present time.
There are four positions on the HPO ring where a substituent
can be introduced. Several hundred HPO derivatives with variable
substitutions at the 1 position have been prepared.6 A range of 2-
substituted HPOs have also been reported, their synthesis starting
from commercially available maltol or kojic acid.7,8 Although the
functional groups at C6 are readily introduced using kojic acid as
starting material,9 this type of compound is of less interest as a
chelating agent as substituents at this position adversely influence
the chelating properties. Modification at C5, a position adjacent to
the bidentate chelating moiety, can have a beneficial effect in influ-
encing the chelating properties of the pyridinones, in a similar
fashion to position 2 substituents.10 However, few synthetic ap-
proaches have been reported for substitution at position 5. This
may be due to the lower reactivity of C5 when compared with that
of C2. For instance, the Mannich reaction readily takes place at C2
of kojic acid at room temperature11 while the corresponding reac-
tion at C5 of 3-benzyloxy-2-methylpyridin-4-one requires reflux-
ing in ethanol for 20 h.12 A reaction analogous to the aldol
condensation at C2 of 3-hydroxy-6-methylpyran-4-one takes place
at room temperature.9 However, C5 of 3-benzyloxy-2-methylpyri-
din-4-one is inert to such reaction. Looker et al.13 have described
the introduction of bromine to position 5 of maltol by reaction
with N-bromosuccinimide (NBS), which can be eventually con-
verted into 5-Br HPO derivatives. In a similar fashion, we suc-
ceeded in synthesising 5-bromo-2-methyl-3-methoxypyridin-4-
one in high yield by adding molecular bromine dropwise to 2-
methyl-3-methoxypyridin-4-one in dichloromethane at room tem-
perature. However, all attempts at direct replacement of the bro-
mine with other nucleophiles, or metalation at position 5 when
the 4-hydroxy group of its tautomer was protected, failed. It ap-
pears to be a considerable challenge to introduce a functional
group at C-5 from the 5-bromo analogue. In 1996, Taylor and
coworkers reported a direct dimethylaminomethylation of HPO
at the C-5.12 In a similar fashion, we succeeded in synthesising a
5-benzyl(methyl)aminomethyl-substituted HPO derivative, fol-
lowed by hydrogenation to obtain a secondary amine, which was
eventually converted into the corresponding amide.9 In this Letter,
we report the synthesis of 5-formyl HPO from its 5-dimethylami-
nomethyl derivative by aerobic oxidation under mild conditions.
Several oxidants have been investigated for the oxidation of 5-
dimethylaminomethyl HPO, such as SO3/pyridine, 3-chloroperben-
zoic acid, hydrogen peroxide, benzoyl peroxide and N-bromosuc-
cinimide, the latter two being used to oxidise tertiary
benzylamines to the corresponding aromatic aldehydes.14,15 How-
ever, none of these oxidants achieved the desired transformation.
Cecchetto et al. reported the catalysed oxidation of benzyldimeth-
ylamines to aldehydes using N-hydroxysuccinimide (NHS) and
Co(II).16 When the tertiary amine 1 was oxidised under the same
conditions, the desired aldehyde 2 was isolated, but only in low
yield (Scheme 1). A slightly lower yield was obtained using N-
hydroxyphthalimide (NHPI) instead of NHS, although NHPI is re-
ported to be a more effective catalyst.16 According to the mecha-
nism described by Cecchetto et al.,16 the oxidation involves a
free-radical reaction, where the N-oxyl radical, generated in situ
from NHPI or NHS, abstracts a hydrogen from the methylene func-
* Corresponding author. Fax: +44 207 848 4800.
E-mail address: robert.hider@kcl.ac.uk (R.C Hider).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.027

1416
Y. M. Ma, R. C Hider / Tetrahedron Letters 51 (2010) 1415–1418
H
O
O
OBn
OBn
NHS
O
N
+
1/2 O2
NH(CH3)2
+
Co(II)
N
H
N
H
1
2
Scheme 1. Synthesis of aldehyde 2 by aerobic oxidation of tertiary amine 1 in the presence of NHS/Co(II).
tion of benzyldimethylamine. Initially we investigated several rad-
ical catalysts as replacements for NHS (Table 1). We selected
2,20,6,60-tetramethylpiperidine-N-oxide (TEMPO) because it has
been reported to catalyse the aerobic oxidation of alcohols into
aldehydes and ketones in the presence of Mn(II)–Co(II) as a co-cat-
alyst.17 However, in our studies with TEMPO, only a trace amount
of the desired aldehyde 2 was detected. When azobisisobutyronit-
rile (AIBN) was investigated, again only low yields (7% and 4% in
the presence or absence of Co(II), respectively) of aldehyde 2 was
found. 2,20-Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride
(VA044), an efficient water-soluble free radical initiator at room
temperature, was also found to be inefficient at catalysing this
conversion.
At this stage we selected NHS as the most promising catalyst and
the same reaction was carried out under various conditions (Ta-
ble 2). Increasing NHS to an equivalent amount did not markedly
improve the yield (run 2). However, a different phenomenon was
observed when the levels of Co(II) were increased to 10% (run 3).
Surprisingly, when both NHS and Co(II) were used in equivalent
amounts, only trace amounts of aldehyde 2 were obtained (run
4). Other transition metal salts, such as those of Cu, Fe, Mn and
Hg, all of which possess two oxidation states, failed to catalyse
the aerobic oxidation, as did Ni, Zn or the absence of a metal salt
(run 5). In contrast, Ce(IV) was found to catalyse the reaction,
although in a lower yield (run 6). Thus it seems most likely that only
the metals possessing high reduction potentials are able to catalyse
the aerobic oxidation. The standard reduction potentials (E0) of
Co(III)/Co(II), Ce(IV)/Ce(III), Mn(III)/Mn(II), Hg(II)/Hg2(II), Fe(III)/
Fe(II) and Cu(II)/Cu(I) are 1.82, 1.61, 1.51, 0.91, 0.77 and 0.16 V,
respectively.18 Apparently, the higher the reduction potential, the
more efficient the catalytic aerobic oxidation.
Table 1
Conversion of tertiary amine 1 to aldehyde 2 by air in the presence of various radical
catalystsa
By increasing the reaction time, the yield was moderately in-
creased. Thus after four days, 29% of aldehyde 2 was obtained
(run 7). The Co(II)–Mn(II) catalytic system together with TEMPO
has been reported to be an efficient catalyst for the conversion of
alcohols into aldehydes in acidic medium.17 However, when this
combined metal catalyst was applied together with NHS to this
oxidation in acetic acid, only a trace amount of the aldehyde was
observed (run 8). When the reaction was carried out in MeCN,
the yield increased but was found to be lower than that with Co(II)
alone (run 9).
Radical
catalyst (%)
Transition
metal salt (%)
Solvent
Temp. (°C) Yield (%)
NHS (10)
Co(II) (1)
Co(II) (1)
Co(II) (1)
Co(II)–Mn(II) (1) Acetic acid
Co(II) (1)
—
MeCN
MeCN
MeCN
50
50
50
50
80
80
22
18
Trace
Trace
7
NHPI (10)
TEMPO (10)
TEMPO (10)
AIBN (100)
AIBN (100)
MeCN
MeCN
MeCN/H2O (1:1) 50
4
VA044 (100) Co(II) (1)
Trace
a
Standard procedure: a solution of 1 mmol of the tertiary amine, a radical cat-
alyst and Co(OAc)2 or a mixture of Co(OAC)2/MnCl2 at the indicated amount in
various solvents in an open test tube was stirred at the indicated temperature for
1 d. The yields were determined by HPLC.
Various solvents have also been tested for the oxidation and we
found that the reaction was not efficient when carried out in protic
Table 2
Oxidation of 3-benzyloxy-5-(dimethylamino)methyl-2-methylpyridin-4(1H)-one into aldehyde 2a
Run
NHS (%)
Transition metal salt (%)
Solvent
Time (d)
Gas
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
10
100
10
100
10
10
10
10
10
10
10
10
10
10
10
10
10
50
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (10)
Co(OAc)2 (100)
None or other metal salts (1)b
(NH4)2Ce(NO3)6 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)+MnCl3 (1)
Co(OAc)2 (1)+MnCl3 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
Co(OAc)2 (1)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
AcOH
MeCN
H2O
MeOH
AcOH
DMF
DMSO
DMF
1
1
1
1
1
1
4
1
1
1
1
1
1
1
1
1
1
5
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Airc
22
23
15
Trace
Trace
9
29
Trace
7
Trace
2
Trace
27
16
23
c
DMF
DMF
DMF
O2
O2
Air
28
22
65d
a
Standard procedure: a solution of the tertiary amine (1 mmol), NHS and transition metal salt in the indicated percentage in various solvents was stirred at 50 °C for the
indicated time in open to air unless otherwise noted. The yields were determined by HPLC.
b
Other metal salts include FeSO4, MnCl2, Hg(OAc)2, NiCl2, Zn(OAc)2 and CuSO4.
The reaction mixture was bubbled with either air or O2.
NHS was added in 5 portions at daily intervals.
c
d

Y. M. Ma, R. C Hider / Tetrahedron Letters 51 (2010) 1415–1418
1417
solvents such as water, methanol and acetic acid (runs 10–12).
Amongst the aprotic solvents (runs 1, 13 and 14), DMF was found
to be the most suitable. We favour DMF, not only because the yield
was slightly higher than that in MeCN, but also because DMF is a
superior solvent for the tertiary amine 1.
When the reaction was carried out in the presence of molecular
O2 at atmospheric pressure or by bubbling with either air or O2
(runs 15–17), the yield was not appreciably different to that of a
reaction mixture being oxidised in the open air. The reaction yield
was markedly improved by prolonging the reaction time to five
days (run 18) when NHS to a total amount of 50% was added five
times at daily intervals. These were by far the best conditions for
achieving a practical yield.19
A plausible mechanism for the oxidation is similar to that de-
scribed by Ishii using NHPI instead of NHS20 and is illustrated in
Scheme 2. Firstly, a superoxocobalt(III) complex is formed by the
oxidation of Co(II) in the presence of O2, which can then assist
the generation of succinimide-N-oxyl (SNO) from NHS. The result-
ing N-oxyl radical abstracts a hydrogen from the tertiary amine to
generate a new radical species which couples with O2 to form a
peroxy radical. This radical can be trapped by either NHS or a sec-
ond tertiary amine to generate an alkyl hydroperoxide which is
eventually converted into the aldehyde. The conversion catalysed
by the redox metal occurs in a similar manner to the Haber–Weiss
cycle Eqs. (1)–(3). The overall process of Eqs. (1)–(3) is given by Eq.
4. It seems that Co(II) plays two key roles in the aerobic oxidation.
Firstly, the presence of a small amount of Co(II) accelerates the
generation of the free radical from N-hydroxyimide by molecular
O2.21 Secondly, the alkyl hydroperoxide generated from alkyl radi-
cals is eventually converted into the aldehyde catalysed by Co(II).
O-
OOH
ð1Þ
Co(III) + ArCHN(CH3)2 + HO
Co(II) + O2
Co(II) + ArCHN(CH3)2
-
ð2Þ
ð3Þ
Co(III) + O2
OOH
OH
ArCHN(CH3)2 + H+ + O2
-
ArCHN(CH3)2
+ HO
OOH
OH
2 ArCHN(CH3)2
O2 + 2 ArCHN(CH3)2
2 ArCHO + 2 (CH3)2NH
ð4Þ
O
N
OH
ArCHO
O
O2
Co(III)
Co(II)
Co(II)
Co(III)OO
1
2
6
Co(III)OOH
Co(III)
O
OOH
N
O
ArCHN(CH3)2
O
ArCH2N(CH3)2
5
O
3
N
OH
5
OO
O
ArCHN(CH3)2
ArCHN(CH3)2
ArCHN(CH3)2
ArCH2N(CH3)2
4
O2
Scheme 2. A plausible mechanism for the aerobic oxidation of a tertiary amine catalysed by NHS and Co(II).
O
O
O
O
O
OH
R
OH
OHC
OBn
R
N
H
N
H
N
R
N
R
N
H
O
R
OH
N
H
N
H
Scheme 3. Conversion of 5-formyl HPO into amido or amino derivatives by conventional methods.

1418
Y. M. Ma, R. C Hider / Tetrahedron Letters 51 (2010) 1415–1418
10. Liu, Z. D.; Khodr, H. H.; Liu, D. Y.; Lu, S. L.; Hider, R. C. J. Med. Chem. 1999, 42,
In summary, various radical catalysts and transition metal salts
4814–4823.
and their molar ratios have been investigated for the aerobic oxida-
tion of 3-benzyloxy-5-(dimethylamino)methyl-2-methylpyridin-
4(1H)-one. Solvent effects have also been monitored. A promising
yield was achieved by adding NHS at daily intervals for a total of
a five-day reaction catalysed by NHS/Co(II) in DMF at 50 °C. The
successful introduction of a formyl group at position 5 of hydroxy-
pyridin-4-one permits ready conversion into other functional
groups such as amines, amino- and carboxyl-terminated amides
using conventional methods (Scheme 3). Such studies are currently
in progress.
11. Obrien, G.; Patterson, J. M.; Meadow, J. R. J. Org. Chem. 1960, 25, 86–89.
12. Patel, M. K.; Fox, R.; Taylor, P. D. Tetrahedron 1996, 52, 1835–1840.
13. Looker, J. H.; Prokop, R. J.; Serbousek, W. E.; Cliffton, M. D. J. Org. Chem. 1979,
44, 3408–3410.
14. Buckley, D.; Dunstan, S.; Henbest, H. B. J. Chem. Soc. 1957, 4901–4905.
15. Sinhababu, A. K.; Borchardt, R. T. J. Am. Chem. Soc. 1985, 107, 7618–7627.
16. Cecchetto, A.; Minisci, F.; Recupero, F.; Fontana, F.; Pedulli, G. F. Tetrahedron
Lett. 2002, 43, 3605–3607.
17. Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F. Tetrahedron Lett. 2001, 42,
6651–6653.
18. Denker, J. S. Standard reduction potentials. http://www.av8n.com/physics/
redpot.htm.
19. A typical example for the oxidation of a tertiary amine on preparative scale: a
solution of 3-benzyloxy-5-(dimethylamino)methyl-2-methylpyridin-4(1H)-
References and notes
one
1 (10 mmol, 2.72 g), N-hydroxysuccinimide (1 mmol, 115 mg) and
cobalt(II) acetate tetrahydrate (0.1 mmol, 24.9 mg) in DMF (30 mL) in an
open vessel was stirred at 50 °C for 5 d with further additions of NHS (total
460 mg) at daily intervals. The solvent was then evaporated and the residue
was purified by silica gel chromatography (eluent: MeOH/CH2Cl2 = 1:9) to
yield 1.44 g of 2 as white crystals. Mp 194–196 °C; 1H NMR (400 MHz, DMSO-
d6) d: 2.07 (s, 3H, CH3), 5.12 (s, 2H, CH2), 7.31–7.44 (m, 5H, Ph), 8.01 (s, 1H,
pyridinone CH), 10.16 (s, 1H, CHO), 12.12 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6) d: 13.57 (CH3), 72.02 (CH2), 122.59 (pyridinone C-3), 127.95 (phenyl
CH), 128.23 (phenyl CH), 128.50 (phenyl CH), 137.47 (phenyl C), 137.73
(pyridinone CH-2), 139.85 (pyridinone C-6), 147.30 (pyridinone C-5), 172.80
(pyridinone C@O), 189.85 (CHO); HRMS: (M+Na)+, calcd for C14H13NO3Na
266.0793. Found 266.0784.
1. Liu, Z. D.; Hider, R. C. Med. Res. Rev. 2002, 22, 26–64.
2. Balfour, J. A. B.; Foster, R. H. Drugs 1999, 58, 553–578.
3. Singh, S.; Epemolu, R. O.; Dobbin, P. S.; Tilbrook, G. S.; Ellis, B. L.; Damani, L. A.;
Hider, R. C. Drug Metab. Dispos. 1992, 20, 256–261.
4. Brittenham, G. M. Blood 1992, 80, 569–574.
5. Olivieri, N. F.; Brittenham, G. M.; McLaren, C. E.; Templeton, D. M.; Cameron, R. G.;
McClelland, R. A.; Burt, A. D.; Fleming, K. A. N. Eng. J. Med. 1998, 339, 417–423.
6. Dobbin, P. S.; Hider, R. C.; Hall, A. D.; Taylor, P. D.; Sarpong, P.; Porter, J. B.; Xiao,
G. Y.; Vanderhelm, D. J. Med. Chem. 1993, 36, 2448–2458.
7. Liu, Z. D.; Kayyali, R.; Hider, R. C.; Porter, J. B.; Theobald, A. E. J. Med. Chem. 2002,
45, 631–639.
20. Ishii, Y.; Sakaguchi, S. Catal. Today 2006, 117, 105–113.
21. Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393–427.
8. Piyamongkol, S.; Liu, Z. D.; Hider, R. C. Tetrahedron 2001, 57, 3479–3486.
9. Ma, Y.; Luo, W.; Quinn, P. J.; Liu, Z.; Hider, R. C. J. Med. Chem. 2004, 47, 6349–6362.